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Molecular Cancer
Published in: Molecular Cancer 1/2015

Open Access 01-12-2015 | Research

Activin and TGFβ use diverging mitogenic signaling in advanced colon cancer

Authors: Jessica Bauer, Ozkan Ozden, Naomi Akagi, Timothy Carroll, Daniel R. Principe, Jonas J. Staudacher, Martina E. Spehlmann, Lars Eckmann, Paul J. Grippo, Barbara Jung

Published in: Molecular Cancer | Issue 1/2015

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Abstract

Background

Understanding cell signaling pathways that contribute to metastatic colon cancer is critical to risk stratification in the era of personalized therapeutics. Here, we dissect the unique involvement of mitogenic pathways in a TGFβ or activin-induced metastatic phenotype of colon cancer.

Method

Mitogenic signaling/growth factor receptor status and p21 localization were correlated in primary colon cancers and intestinal tumors from either AOM/DSS treated ACVR2A (activin receptor 2) −/− or wild type mice. Colon cancer cell lines (+/− SMAD4) were interrogated for ligand-induced PI3K and MEK/ERK pathway activation and downstream protein/phospho-isoform expression/association after knockdown and pharmacologic inhibition of pathway members. EMT was assessed using epithelial/mesenchymal markers and migration assays.

Results

In primary colon cancers, loss of nuclear p21 correlated with upstream activation of activin/PI3K while nuclear p21 expression was associated with TGFβ/MEK/ERK pathway activation. Activin, but not TGFβ, led to PI3K activation via interaction of ACVR1B and p85 independent of SMAD4, resulting in p21 downregulation. In contrast, TGFβ increased p21 via MEK/ERK pathway through a SMAD4-dependent mechanism. While activin induced EMT via PI3K, TGFβ induced EMT via MEK/ERK activation. In vivo, loss of ACVR2A resulted in loss of pAkt, consistent with activin-dependent PI3K signaling.

Conclusion

Although activin and TGFβ share growth suppressive SMAD signaling in colon cancer, they diverge in their SMAD4-independent pro-migratory signaling utilizing distinct mitogenic signaling pathways that affect EMT. p21 localization in colon cancer may determine a dominant activin versus TGFβ ligand signaling phenotype warranting further validation as a therapeutic biomarker prior to targeting TGFβ family receptors.
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Metadata
Title
Activin and TGFβ use diverging mitogenic signaling in advanced colon cancer
Authors
Jessica Bauer
Ozkan Ozden
Naomi Akagi
Timothy Carroll
Daniel R. Principe
Jonas J. Staudacher
Martina E. Spehlmann
Lars Eckmann
Paul J. Grippo
Barbara Jung
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2015
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-015-0456-4

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